Lipids have been used as an integral component of parenteral nutrition over the last four decades. Lipids provide essential fatty acids for cellular structures, specifically cell membranes, and for precursors of prostaglandins, leukotrienes, thromboxanes and other eicosanoids. They constitute a source of energy, take part in various biosynthetic pathways, and are carriers of fat-soluble vitamins. As such, lipids play an important role in metabolic and immune processes, in the development and function of the central nervous system and the retina.
Fatty acids (FA) differ from one another by the number of carbon atoms, their saturation or degree of non-saturation, the positions of unsaturated bonds, and whether these bonds are cis or trans. All of these variables are relevant to the nutritional value or benefit derived from triglycerides containing these acids. In addition, the enzymatic cleavage of the triglycerides is affected by the type and position of the fatty acids on the glycerol backbone.
Fatty acids in general are divided into four groups: short chain FA, medium chain FA (MCFA), long chain FA (LCFA), and very long chain FA (VLCFA). Fatty acids are also classified by the presence, number, and location of double bonds. This classification divides FA into three groups: saturated FA (no double bonds), monounsaturated FA (one double bond) and polyunsaturated FA (2 double bonds and more). Further classification of the polyunsaturated FA is characterized by the placement of the carbon preceding the first double bond from the terminal methyl carbon: n-3 or ω-3 FA, n-6 or ω-6 FA and n-9 or ω-9 FA. These differences determine the various characteristics of FA and therefore their specific functions.
Lipid Emulsions
The need for lipids as essential and integral component of parenteral nutrition (PN) emerged from the observations of the clinical symptoms following use of fat free PN. These clinical symptoms included hemorrhagic dermatitis, skin atrophy, hyperglycemia, weight loss, decrease of immune function, increase of catabolism, etc.
The first generation of lipid emulsions was based on pure long chain triglycerides (LCT) derived from soybean oil and safflower oil. Their administration prevented some of the symptoms of fatty acid deficiency. Nevertheless, patients that received these lipid emulsions showed impaired function of lymphocytes and of the reticuloendothelial system, depressed T-cell counts, increased oxygen free radical production, elevation of liver enzymes, hypertriglyceridemia, and suffered from infections.
The next generation of lipid emulsions contained 50% medium chain triglycerides (MCT) and 50% LCT. These emulsions have many advantages compared to pure LCT emulsions, for example, they are an efficient energy source, they are more soluble, rapidly hydrolyzed by lipases, quickly eliminated from blood, rapidly oxidized, and have smaller particle size. As the MCFA are all saturated, they are not subjected to peroxide formation and therefore they do not impair the immune and reticuloendothelial systems. Patients receiving MCT/LCT emulsions demonstrate a better nitrogen balance and a better protein sparing effect.
Another attempt to overcome the disadvantages of pure LCT emulsions was to use olive oil, rich in monounsaturated oleic acid (18:1 ω-9). Olive oil based emulsions were shown to be well-tolerated, more suitable for preventing lipid peroxidation, and maintained a normal essential FA status. It was also demonstrated that olive oil emulsions contain primarily alpha tocopherol, the more biologically active tocopherol, while soybean oil emulsions contain predominantly gamma tocopherol, which has little protection against lipid peroxidation. When the composition and peroxidation of lipoproteins were compared in children receiving olive oil or soybean oil emulsions, it was found that administration of olive oil emulsions resulted in a decreased oxidative stress. Gobel et al., and Goulet et al., showed the advantages of olive oil emulsions compared to other LCT emulsions in preterm infants and in children (Gobel Y., et al., J. Pediatr. Gastroenterol. Nutr. 37(2): 161-167, 2003; Goulet, O., et al., Am. J. Clin. Nutr. 70(3): 338-345, 1999). Oleic acid, and in general the ω-9 fatty acids, have been shown to contribute to brain development and function as they are a major component of the white matter and myelin.
The beneficial effects of ω-3 fatty acids derived from fish oil in enteral feeding prompted their inclusion in parenteral nutrition. The most successful regimen was achieved by the combination of 50% MCT, 40% soybean oil and 10% fish oil. This regimen demonstrated an improvement in the immune system function of surgical and critically ill patients, an improvement of FA profile in cell membranes, anti-inflammatory and anti-coagulation effects, a normalization of plasma triglycerides (TG) and cholesterol, and a reduction in blood pressure.
Structured Triglycerides
Lipid emulsions containing randomized structured triglycerides (STG) have been obtained by mixing MCT and LCT oils and heating the mixture in the presence of a catalyst. During this process, MCFA and LCFA can be exchanged randomly on the glycerol backbone of both oils. The new TG thus formed contains both long and medium chain FA on the same glycerol, randomly distributed. This kind of triglycerides are rapidly hydrolyzed by lipases, and hence are better cleared from the blood stream.
Many clinical studies have demonstrated the safety and the advantages of STG emulsions. Sandstrom et al., demonstrated that STG emulsions administered to postoperative patients were rapidly cleared from the plasma, rapidly oxidized, and were not associated with any side effects (Sandstrom, R., et al., JPEN 19 (5): 381-386, 1995). Provision of STG caused a significantly higher whole body fat oxidation compared to LCT. Rubin et al, demonstrated that STG appear to be safe and well tolerated on a long term basis in patients on home parenteral nutrition and suggested that STG emulsions may be associated with possible reduction in liver dysfunction (Rubin, M., et al., Nutrition, 16: 95-100, 2000).
Kruimel et al., compared the effect of STG versus physical mixture of MCT and LCT on the nitrogen balance of moderately catabolic postoperative patients. Over a period of 5 days the cumulative nitrogen balance was less negative in the STG group (Krumiel, J. W., et al., JPEN 25(5): 237-244, 2001). This difference can be explained by better utilization of the STG fatty acids for energy and better clearance from the blood (ibid.). Chambrier et al., compared the effect of STG vs. a physical mixture of MCT-LCT on liver function in postoperative patients. A significant increase in liver enzymes and in plasma TG was found to occur in patients administered with the physical mixture of MCT-LCT, while no changes in liver function nor in plasma TG level were found to occur in patients administered with STG (Chambrier, C., et al., Nutrition, 15: 274-277, 1999).
U.S. Pat. No. 4,871,768 discloses a synthetic triglyceride comprising a glycerol backbone having three fatty acids attached thereto, wherein at least one fatty acid is selected from ω3 fatty acids and at least one fatty acid is selected from C8-C10 fatty acids. The ω3 fatty acids are derived from plant oils, marine plankton oils, fungal oils, or fish oils. U.S. Pat. No. 4,871,768 also discloses a dietary supplement comprising 10 to 40% by weight of an oily fraction, the oily fraction comprises 10 to 90% by weight of the synthetic triglyceride. The synthetic triglyceride in the dietary supplement according to U.S. Pat. No. 4,871,768 further comprises ω9 fatty acids. Yet, the necessity of docosahexaenoic acid (DHA) and arachidonic acid in the synthetic triglyceride, and the necessity of vitamin E in the dietary supplement have not been indicated nor the optimal ratio of ω6 to ω3.
U.S. Pat. No. 4,906,664 discloses a method for providing nutritional support to patients suffering from cancer cachexia. The method comprises the step of parenteral administration of a diet containing a structured lipid. The structured lipid according to U.S. Pat. No. 4,906,664 is a triglyceride wherein at least one of the chains is a medium chain fatty acid, at least one of the chains is an ω3 long chain fatty acid, and the other chain is selected from the group consisting of medium chain fatty acids and long chain fatty acids. The ratio of long chain fatty acids to medium chain fatty acids is about 1:1. The long chain fatty acids should be primarily ω3 and ω6 fatty acids, with sufficient ω6, preferably in the form of linoleic acid.
U.S. Pat. No. 5,081,105 discloses a method of treating sarcomas in a patient through the use of nutritional support therapy comprising the step of parenterally administering a diet including a structured lipid. The structured lipid according to U.S. Pat. No. 5,081,105 is a triglyceride where one of the chains is a medium chain fatty acid, a second chain is a ω3 fatty acid, and the third chain is selected from H, OH, short, medium, and long fatty acids.
U.S. Pat. No. 5,962,712 discloses a family of structured lipids, one of the fatty acid residues is selected from the group consisting of gamma linolenic acid (GLA) and dihomogamma linolenic acid (DHGLA). A second fatty acid residue is selected from C18-C22 n-3 fatty acids, and the third fatty acid residue is selected from C6-C12 fatty acids. The simultaneous presence of C18-C22 n-3 fatty acid residues and GLA or DHGLA may serve to minimize the elongation of GLA and DHGLA to arachidonic acid. The long chain polyunsaturated n-3 fatty acids will purportedly shift the prostaglandin metabolism away from pro-inflammatory prostanoids to non-inflammatory prostanoids, having beneficial effects in treating inflammation and infection. U.S. Pat. No. 5,661,180 discloses a method of modulating metabolic response to trauma and disease states in a patient comprising the step of administering a dietary structured lipid as disclosed in U.S. Pat. No. 5,962,712.
There is an unmet need for structured triglycerides designed to provide improved enteral or parenteral nutrition, which is easily assimilated by infants, children, and patients suffering severe stress or chronic illness and which is optimized to address developmental and immunological needs.